Modern cancer therapy largely involves the use of radiation, surgery and chemotherapeutic agents. However, results with these measures, while beneficial in some tumors, has had only marginal or no effect in many others. Furthermore, these approaches often have unacceptable toxicity.
Both radiation and surgery suffer from the same theoretical drawback. It has been recognized that, given that a single clonogenic malignant cell can give rise to sufficient progeny to kill the host, the entire population of neoplastic cells must be eradicated. See generally, Goodman and Gilman The Pharmacological Basis of Therapeutics (Pergamon Press, 8th Edition) (pp. 1202-1204). This concept of “total cell kill” implies that total excision of a tumor is necessary for a surgical approach, and complete destruction of all cancer cells is needed in a radiation approach, if one is to achieve a cure. In practice this is rarely possible; indeed, where there are metastases, it is impossible.
Moreover, traditional chemotherapeutic cancer treatments also rarely result in complete remission of the tumor, and the significant dosage levels required to generate even a moderate response are often accompanied by unacceptable toxicity. Anticancer agents typically have negative hematological effects (e.g., cessation of mitosis and disintegration of formed elements in marrow and lymphoid tissues), and immunosuppressive action (e.g., depressed cell counts), as well as a severe impact on epithelial tissues (e.g., intestinal mucosa), reproductive tissues (e.g., impairment of spermatogenesis), and the nervous system. P. Calabresi and B. A. Chabner, In: Goodman and Gilman The Pharmacological Basis of Therapeutics (Pergamon Press, 8th Edition) (pp. 1209-1216). The high dosage levels, and the resulting toxicity, are in large part necessitated by the lack of target specificity of the anticancer agents themselves. The drug needs to distinguish between host cells that are cancerous and host cells that are not cancerous. The vast bulk of anticancer drugs are indiscriminate at this level, and have significant inherent toxicity.
Success with standard chemotherapeutics as anticancer agents has also been hampered by the phenomenon of multiple drug resistance, resistance to a wide range of structurally unrelated cytotoxic anticancer compounds. J. H. Gerlach et al., Cancer Surveys, 5:25-46 (1986). The underlying cause of progressive drug resistance may be due to a small population of drug-resistant cells within the tumor (e.g., mutant cells) at the time of diagnosis. J. H. Goldie and Andrew J. Coldman, Cancer Research, 44:3643-3653 (1984). Treating such a tumor with a single drug first results in a remission, where the tumor shrinks in size as a result of the killing of the predominant drug-sensitive cells. With the drug-sensitive cells gone, the remaining drug-resistant cells continue to multiply and eventually dominate the cell population of the tumor.
Treatment at the outset with a combination of drugs was proposed as a solution, given the small probability that two or more different drug resistances would arise spontaneously in the same cell. V. T. DeVita, Jr., Cancer, 51:1209-1220 (1983). However, it is now known that drug resistance is due to a membrane transport protein, “P-glycoprotein,” that can confer general drug resistance. M. M. Gottesman and I. Pastan, Trends in Pharmacological Science, 9:54-58 (1988). Phenotypically, the tumor cells show, over time, a reduced cellular accumulation of all drugs. In short, combination chemotherapy appears not to be the answer.
Adoptive cellular immunotherapy has been proposed as an alternative treatment methodology, using the body's own immune system in an attempt to improve target cell specificity while reducing toxicity. The activation and proliferation of various lymphocyte populations with lymphokines both in vivo and in vitro has been investigated, with mixed degrees of success. For example, lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TILs) have both been used in combination with interleukin-2 (IL-2) in the treatment of metastatic disease. See Rosenberg et al., N. Engl. J. Med. 316:889-97 (1987); Belldegrun et al., Cancer Res. 48:206-14 (1988).
Unfortunately, the inclusion of high levels of IL-2 to activate and expand the cell populations is itself associated with significant toxicity to the patient. Moreover, target-cell specific cell populations have been difficult to expand in vitro, since lymphocytes cultured in high levels of IL-2 eventually develop an unresponsiveness to IL-2, and subsequently exhibit a serious decline in proliferation and cytotoxicity. See Schoof et al., Cancer Res. 50:1138-43 (1990). The latter problem has also impeded efforts to successfully use lymphocytes as cellular vehicles for gene therapy in man.
What is needed is a specific anticancer approach that is reliably tumoricidal to a wide variety of tumor types. Importantly, the treatment must be effective with minimal host toxicity.